Dissertations / Theses on the topic '2-DPA'

Serrated tussock (Nassella trichotoma) and Giant Parramatta Grass (Sporobolus fertilis) are among the most noxious weeds in Australia. Both cause problems in pasture and there are limited control measures relying heavily on the herbicide flupropanate. With the recent confirmation of flupropanate resistance in serrated tussock and the report of suspected flupropanate resistance in Giant Parramatta Grass (GPG), this option appeared to be under threat.The aims of this thesis were to determine the extent of flupropanate resistance in serrated tussock and GPG in Australia and to understand the genetics of flupropanate resistance in serrated tussock. This thesis also documents the GPG resistance to 2,2-DPA and investigates a fungal pathogen, Nigrospora oryzae, as a potential biocontrol agent for GPG. A local paddock survey determined the spread and extent of flupropanate resistance in serrated tussock within 5 km of the original resistant site. The pot-dose method of assessing resistance identified plants resistant to flupropanate up to 3.5 km from the original site found in Victoria. Seeds from these plants showed 0-100% resistance, with sensitive plants often having a low („T5%) level of resistant seed. These results indicate the movement of flupropanate resistance through seeds or pollen and shows that its spread occurred within one year of detection. A national mail survey confirmed the massive impacts of serrated tussock across Australia, with annual serrated tussock costs ranging from $15,000 to $16,000 per year per respondent. This survey also identified the widespread infestation of this weed in a variety of land use patterns, from pasture to native grasslands, and the decrease in the value of farmland as a result. Heritability studies using controlled breeding experiments indicated a strong involvement of a maternal component in the inheritance of flupropanate resistance in serrated tussock, with a minor proportion of resistance heritable through pollen. GPG plants and seedlings were tested for flupropanate and 2,2-DPA resistance.Seedlings tested for flupropanate resistance were highly resistant (tolerating 33-39 times more than sensitive biotypes). With 2,2-DPA, resistant GPG plants did not die even at 14 times the field rate and resistant seedlings also showed 5-6 times more resistance than the sensitive biotype. The study has confirmed that flupropanate and 2,2-DPA resistance now exists in GPG.The potential of Nigrospora oryzae, a pathogenic fungus, as a biocontrol agent for GPG was determined. Mature plants and seedlings of GPG were inoculated with conidia of N. oryzae using three treatments (run-off, crown, and spray). Inoculated plants were smaller, with greater proportions of dead leaves (70% with the run-off a nd crown treatments and 53% with the spray treatment) than the control plants. GPG seedlings inoculated with N. oryzae were stunted and showed greater proportions of necrotic leaves in all the treatments than the control. There is potential to develop N. oryzae as a mycoherbicide to control GPG and further testing is warranted.

The novel compound [Ru(bpy)(dpb)â (PFâ )â was synthesized, in a manner similar to the literature synthesis of [Ru(bpy)(dpq)â (PFâ )â . For the sake of completeness, the related analogs, [Ru(bpy)â (dpb)](PFâ )â , [Ru(bpy)â (dpq)](PFâ )â and [Ru(bpy)(dpq)â ](PFâ )â were also synthesized. Alumina adsorption chromatography was used for purification purposes. Liquid secondary ion mass spectroscopy was used to confirm identity of compounds. The new compound contained 1% electroactive impurity as determined by OSWV. Spectroelectrochemical studies were conducted with both a bulk H-cell and a ~0.2 mm pathlength, optically transparent thin layer electrode (OTTLE) cell. High reversibility (a 99%) is possible with dilute solutions (ca 10⠻⠴ M) and the OTTLE cell as compared to ca 50% with the H-cell. Spectroelectrochemical data supported the following electronic transitions for the new compound [Ru(bpy)(dpb)â ](PFâ )â : (1) the Ru (dÏ ) â dpb MLCT at 552 nm, (2) a d â d at 242 nm, a bpy Ï â Ï * at 285 nm. (3) The location of the Ru (dÏ ) â bpy MLCT peak is obscured by shoulders from 390-420 nm. (4) The strong peak at 316 nm may be dpb Ï â Ï â *, the location of the lower energy intraligand dpb Ï â Ï â * is uncertain. Upon oxidation of the metal center, no LMCT was observed within the UV-VIS range. This is in direct contrast to the results of Gordon et al. This author hypothesizes that their LMCT found in the visible region was actually the result of incomplete electrochemical conversion and that a LMCT should be seen in the NIR. The spectroelectrochemical properties of [Ru(bpy)(dpq)â ](PFâ )â were also presented for the first time. These results indicated that the 256 nm transition was d â d and not bpy Ï â Ï â * as suggested by Rillema et al.
Master of Science

Developments in high-performance computing instruments and advancements in the numerical algorithms combined with lattice gauge theory make it possible to simulate Quantum Chromodynamics (QCD), the theory of strongly-interacting quarks and gluons, numerically at nearly physical light-quark masses. In this work we present our results for the $D^*Dpi$ coupling constant as simulated on $32^3 imes 64$, unquenched $2+1$-flavor lattices. We estimate the coupling at the chiral limit as $g_{D^*Dpi} = 16.23 pm 1.71$, which is in good agreement with its experimental value $g^{(exp)}_{D^*Dpi} = 17.9pm0.3pm1.9$ as obtained by CLEO II Collaboration.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Diabetes mellitus is a metabolic disease characterized by hyperglycemia due defective or deficient response to insulin secretion. Type 2 diabetes mellitus (Type 2 DM) is therefore associated with a general activation of the innate immune system, in which there is a chronic, cytokine-mediated state of low-grade inflammation. Dipeptidyl peptidase IV (DPP-IV) is a cell-surface protease that bind with Adenosine deaminase (ADA) and both enzymes act in the lymphocytes proliferation and citokyne production. Vitis vinifera is a plant that has been studied due its pharmacology effects including the hypoglycemic properties. Thus, the aim of this study is to evaluate some inflammatory biomarkers, the ADA and DPP-IV activities in type 2 DM and investigate the effects of aqueous grape seed extract from Vitis vinifera (cv. Merlot) (GSE) in the ADA and DPP-IV activities in lymphocytes submitted to different glucose concentrations, in vitro. In the manuscript I, in lymphocytes, we observed a decrease in CD26 expression, an increase in ADA and n-acetil-β-d-glucosaminidase (NAG) activities in type 2 DM patients when compared to controls, while the gamma-glutamyl tranferase (GGT) and DPP-IV activities did not show differences between the groups. Moreover, the NAG activity demonstrated a positive correlation with ADA activity and a negative, with CD26 expression. GGT activity was positively correlated with waist circumference and body mass index (BMI), in type 2 DM. In the manuscript II, we observed we observed an increase in ADA activity when lymphocytes were exposure to the high concentration (100mM) of glucose and GSE prevented this increase in ADA activity. In serum, in the manuscript I, we showed an increase in ADA activity and in C reactive protein (CRP) levels in type 2 DM. Furthermore, the levels of CRP in diabetics were positively correlated with waist circumference and BMI. The GGT and DPP-IV activities did not show alterations between the groups, but in type 2 DM the DPP-IV activity was positively correlated with glicated hemoglobin. We concluded that, glucose might stimulated the ADA activity in the same time that it cause decrease in CD26 expression, in lymphocytes. Moreover, GSE prevents the ADA activation in presence of glucose possible due its hypoglycemic properties.
O diabetes melito (DM) é uma desordem metabólica caracterizada por hiperglicemia em virtude de resposta defeituosa ou deficiente à secreção de insulina. O DM tipo 2 (DM 2) está associado com a ativação do sistema imune, no qual há uma inflamação de baixo grau mediada por citocinas. A dipeptidil peptidase IV (DPP-IV, CD26) é uma protease multifuncional e na superfície celular ela encontra-se ligada a adenosina deaminase (ADA). Ambas estão envolvidas na proliferação de linfócitos e na produção de citocinas inflamatórias. A Vitis vinifera é uma planta que tem sido estudada devido suas propriedades farmacológicas, dentre essas, por apresentar efeitos hipoglicêmiantes. Desta forma, o objetivo deste estudo foi avaliar biomarcadores inflamatórios, a atividade da ADA e da DPP-IV em pacientes com DM 2, e verificar o efeito do extrato aquoso de sementes de Vitis vinifera (cv. Merlot) sobre a atividade da ADA e da DPP-IV em linfócitos expostos a diferentes concentrações de glicose, in vitro. Em linfócitos, no manuscrito I observamos uma diminuição na expressão do CD26, um aumento na atividade da ADA e da n-acetil-β-d-glicosaminidase (NAG) em pacientes com DM 2 em relação aos controles, enquanto que a atividade da gamaglutamil transferase (GGT) e da DPP-IV não se alterou. Também, a atividade da NAG linfocitária em pacientes com DM 2 mostrou-se positivamente relacionada com a atividade da ADA e negativamente com a expressão do CD26 e a atividade da GGT mostrou-se positivamente relacionada à circunferência abdominal e ao IMC. Já no manuscrito II, observamos um aumento na atividade da ADA quando os linfócitos forma expostos a 100mM de glicose e este aumento foi atenuado quando, expostos a glicose e extrato aquoso de sementes de Vitis vinifera. Em soro, no manuscrito I, observamos um aumento na atividade da ADA e também nos níveis de proteína C reativa (PCR) em pacientes com DM 2. Além disso, os níveis de PCR em diabéticos mostraram-se positivamente correlacionados com a circunferência abdominal e o índice de massa corporal (IMC) desses pacientes. A atividade da GGT e da DPP-IV não mostraram diferenças entre os grupos. No entanto, a atividade da DPP-IV sérica mostrou-se correlacionada com os níveis de hemoglobina glicada nos pacientes com DM 2. Conclui-se que, a glicose possa estimular a atividade da ADA ao mesmo tempo em que provoca uma redução da expressão do CD26 em linfócitos. Além disso, o extrato aquoso de sementes de Vitis vinifera é capaz de impedir a ativação da atividade da ADA em presença de glicose possivelmente devido suas propriedades hipoglicemiantes.

Implementation of the polyphase decomposed FIR filter structure involves two steps; the generation of the partial products and the efficient reduction of the generated partial products. The partial products are generated by a constant multiplication of the filter coefficients with the input data and the reduction of the partial products is done by building a pipelined adder tree using FAs and HAs. To improve the speed and to reduce the complexity of the reduction tree a4:2 counter is introduced into the reduction tree. The reduction tree is designed using a bit-level optimized ILP problem which has the objective function to minimize the overall cost of the hardware used. For this purpose the layout design for a 4:2 counter has been developed and the cost function has been derived by comparing the complexity of the design against a standard FA design. The layout design for a 4:2 counter is implemented in a 65nm process using static CMOS logic style and DPL style. The average power consumption drawn from a 1V power supply, for the static CMOS design was found to be 16.8μWand for the DPL style it was 12.51μW. The worst case rise or fall time for the DPL logic was 350ps and for the static CMOS logic design it was found to be 260ps. The usage of the 4:2 counter in the reduction tree infused errors into the filter response, but it helped to reduce the number of pipeline stages and also to improve the speed of the partial product reduction.

L'épithélium intestinal est en constant renouvellement et les mécanismes qui contrôlent la prolifération y sont parfaitement orchestrés. Le facteur de transcription E2F4 est un régulateur clé de la transition G1/S, de la prolifération et de l'homéostasie des cellules épithéliales intestinales. Contrairement à E2F1, la localisation cellulaire d'E2F4 varie en fonction de l'état prolifératif des cellules : il est exprimé majoritairement au cytoplasme des cellules quiescentes ou différenciées et au noyau des cellules prolifératives. Dans cette thèse, les mécanismes de contrôle de la localisation d'E2F4, de sa phosphorylation et de son expression, de même que les mécanismes qui contrôlent l'entrée en phase S des cellules épithéliales intestinales normales humaines (HIEC) ont été analysés. Nos résultats démontrent que l'activation de la signalisation MEK/ERK par le sérum est requise pour la translocation nucléaire d'E2F4 et la transition G 1/S des HIEC. Par contre, la stimulation du sentier MEK/ERK par l'EGF n'est pas suffisante à induire ces événements: l'inhibition concomitante des GSK3?/? ou des p38?/? est aussi requise. En effet, la combinaison de l'EGF ou du FGF9 avec un inhibiteur pharmacologique des GSK3 entraîne la translocation nucléaire d'E2F4 et l'entrée en phase S. De manière analogue, l'inhibition des p38 en combinaison avec l'EGF cause aussi la translocation nucléaire d'E2F4 et l'entrée en phase S des HIEC. Par ailleurs, l'activation des IKK?/? semble aussi requise pour la translocation nucléaire d'E2F4 et la transition G1/S des HIEC induites par le sérum. Ensuite, nos résultats indiquent qu'E2F4 est rapidement phosphorylé suivant la stimulation par le sérum de manière dépendante du sentier MEK/ERK. Ainsi, des essais kinases in vitro démontrent qu'ERK1 phosphoryle efficacement E2F4, potentiellement sur les S244 et S384. Nos résultats suggèrent aussi que GSK3? interagit avec E2F4, principalement dans les cellules quiescentes, et pourrait alors le phosphoryler. Par ailleurs, E2F4 est phosphorylé, surexprimé et localisé au noyau des adénomes colorectaux humains. De plus, les mutants d'E2F4 retrouvés dans les cancers colorectaux avec instabilité des microsatellites, E2F4(Ser) 12 et E2F4(Ser)14 , sont plus fortement exprimés en raison d'une stabilité accrue et ont une meilleure activité transcriptionnelle. Nous démontrons aussi l'existence de 2 formes principales du partenaire d'interaction d'E2F4, DP-2, exprimées dans les HIEC: DP-2 40 , dont l'expression augmente avec l'entrée en phase S et DP-266 , dont l'expression diminue. De plus, DP-2 40 est surexprimée dans les cancers colorectaux humains et pourrait alors y favoriser la localisation nucléaire d'E2F4. En conclusion, nous avons identifié des mécanismes de régulation du facteur de transcription E2F4 et de l'entrée en phase S des HIEC. Cependant, ces mécanismes sont altérés lors de la carcinogenèse. D'ailleurs, la surexpression et la localisation aberrante d'E2F4 de même que la surexpression de DP-2 40 dans les cancers colorectaux pourraient contribuer à l'hyperprolifération et à la formation de cancers dans le côlon et le rectum. [symboles non conformes]

Tesis para optar al Grado de Doctor en Química
La depresión es una grave patología neuropsiquiátrica caracterizada por síntomas de orden afectivo, cognitivo, motor y somático, la cual es desencadenada por una compleja interconexión de factores genéticos, de desarrollo y medioambientales. Los desórdenes depresivos se encuentran entre las causas más importantes de muerte y discapacidad tanto en los países industrializados como en los países en vías de desarrollo. Se ha propuesto que en los episodios depresivos existe una deficiencia en la neurotransmisión serotoninérgica, sugiriendo de esta forma que la serotonina (5-hidroxitriptamina, 5-HT) sería el principal neurotransmisor involucrado en esta patología. La 5-HT es un neurotransmisor que se encuentra en el sistema nervioso central (SNC) y en el sistema nervioso periférico de muchas especies, y está involucrado en una amplia variedad de procesos fisiológicos y patológicos. A la fecha se ha confirmado la existencia de al menos catorce subtipos de receptores de 5-HT. Dentro de los receptores de 5-HT, el subtipo 5-HT1A (un receptor acoplado a proteína G, GPCR) es el mejor estudiado y caracterizado. Múltiples estudios fisiológicos, clínicos, conductuales y farmacológicos han involucrado a este receptor en una amplia variedad de funciones tales como termorregulación y función neuroendocrina, comportamiento sexual, memoria, función inmune, comportamiento agresivo, depresión y ansiedad entre otras. Sin embargo a causa de la afinidad cruzada de diversos ligandos del receptor 5-HT1A por el receptor 5-HT7, muchas de las funciones atribuidas en primera instancia al receptor 5-HT1A deben ser revisadas. Se cree que la regulación del receptor 5-HT1A es esencial en la respuesta antidepresiva. Estos receptores se encuentran localizados presinápticamente en el núcleo del rafe dorsal, donde actúan como autoreceptores somatodendríticos para inhibir la velocidad de disparo de las neuronas serotoninérgicas, y están localizados postsinápticamente en las regiones corticales y límbicas, donde actúan atenuando la actividad de disparo a través de circuitos de retroalimentación neuronal entre las áreas de proyección del cortéx y amígdala. Los tratamientos farmacológicos para la depresión aumentan la biodisponibilidad de 5-HT a través del bloqueo de su recaptación por los terminales nerviosos en distintas estructuras del SNC. Este aumento en los niveles de 5-HT ocurre rápidamente, sin embargo, el inicio del efecto terapéutico tarda de 2-6 semanas en hacerse efectivo con los fármacos actuales. La investigación actual contra la depresión se centra en el desarrollo de fármacos híbridos que inhiban la recaptación de 5-HT y exhiban un antagonismo sobre los autoreceptores somatodendríticos 5-HT1A con el propósito de acelerar el inicio del efecto terapéutico. Existe una amplia variedad de moléculas que presentan afinidad en los receptores 5-HT1A tales como aminotetralinas, indolilalquilaminas, ergolinas y arilpiperazinas entre otras. Las arilpiperazinas representan la clase de ligandos más grande y exhaustivamente estudiada del receptor 5-HT1A. En este sentido el objetivo principal de este trabajo es aportar al conocimiento en relación con moléculas con potencial acción antidepresiva; mediante estudios de síntesis, afinidad serotoninérgica y modelamiento molecular de una serie de nuevos derivados de 2-oxoalquil(4-arilpiperazinil)]-benzo[b]tiofeno sustituido (I), (II) y (III). El diseño de las moléculas se basó en el acoplamiento de diversas arilpiperazinas sustituidas con estructuras relacionadas a la inhibición de la recaptación de serotonina (γ-ariloxipropilaminas). Se estudió la influencia sobre la afinidad al receptor 5-HT1A, de diversas sustituciones en el anillo aromático unido a piperazina (en términos de tamaño, posición y carácter electrónico) y de sustituyentes dadores de electrones (metoxilo) sobre el anillo de benzo[b]tiofeno. Mediante síntesis asistida por microondas se llevó a cabo la síntesis de 18 compuestos (pertenecientes a las familias (I), (II) y (III)) con buenos rendimientos (38 88%). La afinidad de estos compuestos por los receptores serotoninérgicos afines a 8-hidroxi-2-(N,N-di-n-propilamino)tetralina (8-OH-DPAT) se evaluó in Vitro mediante estudios de competencia frente a [3H]-8-OH-DPAT utilizando membranas de corteza cerebral de rata. Los compuestos 1-(benzotiofen-2-il)-3-(4-(piridin 2-il)piperazin-1-il)propan-1-ona (2.27) y 1-(benzotiofen-2-il)-3-(4-(2-metoxifenil)piperazin-1-il)propan-1-ona (2.25) exhibieron los mejores porcentajes de inhibición de la unión de [3H]-OH-DPAT en los estudios de competencia con un 60 y un 52% respectivamente. El compuesto 2.27 exhibió un IC50 de 2,50 µM y una constante de inhibición (Ki) de 2,30 µM. Adicionalmente se determinó la presencia de 2 sitios de unión para [3H]-8-OH-DPAT en las membranas de corteza cerebral de rata. Los valores obtenidos de Kd y Bmáx fueron 0,47 ± 0,17 nM y 1,11 ± 0,19 fmol/mg proteína; y 55,54 ± 12,40 nM y 31,86 ± 3,49 fmol/mg proteína respectivamente. Estos sitios de unión correlacionan bien con los receptores serotoninérgicos 5-HT1A y 5-HT7. Este hallazgo pone en entredicho anteriores estudios que informaban la existencia de una población homogénea de receptores de 5-HT afines a 8-OH-DPAT en corteza cerebral de rata. Con el fin de racionalizar los resultados de los experimentos de competencia se realizó un estudio del acoplamiento molecular (docking) entre los compuestos evaluados y un modelo por homología de la estructura 3D del receptor 5-HT1A. Las interacciones electrostáticas atractivas observadas (puentes de hidrógeno entre el N-1 y el N-4 protonados del compuesto con el D116 y N185 del receptor respectivamente) para el complejo ligando-receptor del compuesto 2.27 explicarían en parte la afinidad observada para este compuesto. Por otra parte, la presencia de un sustituyente en posición 4 del anillo aromático unido a piperazina se mostró perjudicial para la unión de los compuestos al receptor (2.8, 2.12, 2.15 y 2.26), especialmente en el caso de un sustituyente nitro (2.9y 2.26) debido probablemente a su mayor volumen y carácter electronegativo. Este hecho fue confirmado por la presencia de interacciones repulsivas en el complejo ligando-receptor entre el sustituyente y los residuos L179 y N185 del sitio de unión. Los valores de energías de docking observados para los distintos complejos ligandoreceptor correlacionan de forma directa con la afinidad exhibida por los compuestos en los estudios de competencia. Estos resultados podrían ser extrapolables al receptor 5-HT7, dada la alta conservación de los residuos presentes en el sitio de unión de ambos receptores. Los estudios efectuados en esta tesis muestran que el compuesto 2.27 perteneciente a la familia (III), constituye un punto de partida para nuevas modificaciones estructurales en busca de mejorar la afinidad en el receptor 5-HT1A.

Introdução: A sitagliptina, inibidor da dipeptidil-peptidase IV, impede a degradação do GLP-1 (peptídeo-1 semelhante ao glucagon), um dos principais hormônios incretínicos. A dieta interfere na secreção de GLP-1, no entanto, a interação das drogas que aumentam o GLP-1 e os macronutrientes da dieta é pouco estudada. Objetivo e Métodos: Determinar o efeito da sitagliptina, na secreção de GLP-1, glucagon, insulina, peptídeo-C, ácidos graxos livres e na glicemia após três dietas, isocalóricas, de diferentes composições nutricionais em pacientes diabéticos tipo 2, recém-diagnosticados, virgens de tratamento, quando comparado a uso de placebo. Dezesseis indivíduos nessas condições foram submetidos a dietas hiperglicídica, hiperprotêica e hiperlipídica, isocalóricas entre si. Dosaram-se nos tempos 0, 30, 60, 120 e 180 minutos os parâmetros: glicose, insulina, peptídeo C, GLP-1, glucagon e AGL. Foi calculada média de área sob a curva e cálculo da área incremental, além de análise de variância para medidas repetidas. Resultados: Durante o teste de dieta hiperglicídica a glicemia foi maior em todos os tempos quando comparado aos testes com PTN e LPD independentemente do uso de sitagliptina (p<0,05). Sitagliptina diminuiu a glicemia em todos os tempos, quando comparado ao uso de placebo (p<0,05). Durante a dieta CHO, a secreção de glucagon foi menor que nas dietas LPD e PTN (p<0,05). Já a concentração de insulina foi maior com a dieta CHO em relação à dieta LPD (p<0,05). A concentração de insulina e peptídeo C foi maior em todos os tempos na dieta CHO (p<0,05). A concentração de GLP-1 foi significativamente maior durante o teste hiperlipídico em relação à dieta CHO. Durante a dieta LPD, a medida de GLP-1 foi maior em todos os tempos. A dieta CHO apresentou medida de GLP-1 menor em todos os tempos do que as outras dietas (p<0,05). A medida de GLP-1 no tempo foi maior (até 120\') com o uso de sitagliptina do que com o uso do placebo, apesar de não estatisticamente significativa. Os níveis de AGL no tempo foram maiores com o uso do placebo do que com o uso da sitagliptina, apesar de não estatisticamente significativo. Conclusão: Houve diminuição da glicemia em todos os tempos com sitagliptina, independentemente da dieta testada. Houve diminuição do efeito da sitagliptina durante o uso da dieta hiperglicídica
Background: Sitagliptin, a dipeptidil-peptidase IV inhibitor, prevents the degradation of GLP-1 (glucagon-like peptide 1), one of the incretin hormones. It is well-known that diet interferes in the GLP-1 secretion; however, the interaction between drugs that stimulates the release of GLP-1 and the macronutrients from diet is hardly studied. Objective and Methods: To demonstrate the effect of sitagliptin on glycemia, and on the secretion of GLP-1, glucagon, insulin, C-peptide, and free fatty acids after three isocaloric diets with different nutritional compositions, in drug-naïve patients, newly diagnosed with type 2 diabetes, when compared to the use of placebo. Sixteen individuals were subjected to a high-carbohydrate diet, a high-protein diet, and a high-fat diet, all of which with similar caloric values. At 0, 30, 60, 120 and180 minutes after the diet, glucose, insulin, C-peptide, GLP-1, glucagon, and AGL were measured. The mean area under the curve, the incremental area, and the variance for repeated measures were calculated. Results: During high-carbohydrate diet, glycemia was higher for all time points, when compared to the PTN and LPD diets, independently of sitagliptin (p<0,05). Sitagliptin reduced glycemia during three diets when compared to placebo (p<0,05). During CHO diet, secretion of glucagon was smaller than it was during the LDP and PTN diets (p<0,05). On the other hand, insulin concentration was higher than during the LPD diet (p<0,05). Concentrations of insulin and C-peptide were higher for all the time points during the CHO diet (p<0,05). GLP-1 concentration was significantly higher during the high-fat diet than during the high-carbohydrate diet. During the LPD diet, the quantity of the GLP-1 was larger for all time points. The CHO diet presented lower GLP-1 level, for all the time points, than the other diets (p<0,05). The GLP-1 level (up to 120min) with the use of sitagliptin was higher with LPD and PTN diet than it was with the CHO diet. The AGL levels for all time points were higher with placebo than with sitagliptin, although not statistically significant. Conclusion: There was a reduction in glycemia with sitagliptin, independently of the diet tested, for all time points. There was a reduction in sitagliptin effect during the use of the high-carbohydrate diet

碩士
國立臺灣大學
化學研究所
105
This study discuss the arrangement and electricity of two one-dimensional metal string molecules [Ni3(dpa)4(NCS)2] and [Ni11(bnatpya)4(NCS)2]4+ which are different lengths on the Au(111) surface. Sample preparation and surface analysis were obtained by ultrahigh vacuum scanning tunneling microscope (UHV-STM). The samples were prepared by dissolving the metal string molecular with the CH2Cl2 solvent, then drop on the surface of Au(111) and obtaining the [Ni3(dpa)4(NCS)2]/Au(111) and [Ni11(bnatpya)4(NCS)2]4+/Au(111). In the first part, the STM image shows that [Ni3(dpa)4(NCS)2] is adsorbed on the step edge of Au(111) surface, and the height of single metal string molecule could obtained from the height profile. The dI/dV spectra of [Ni3(dpa)4(NCS)2] on Au(111) revealed two characteristic peaks, −0.65 eV and −0.10 eV by the scanning tunneling spectroscopy (STS) .To make sure the molecular characteristics from the image, using the longer molecules of [Ni11(bnatpya)4(NCS)2]4+ to drop on the surface, and the STM image shows the molecules are disorderly and distributed on the surface with one or more repeating monomers by the coffee ring effect. The dI/dV spectrum on the cluster and the single molecule, respectively, the results show that the cluster has a broad peak at the negative bias. In the second part, the chamber is cooled to 78 K to reduce the influence of the thermal disturbance of the molecule and the tip. From the STM images, the electron cloud of single metal string molecule exhibits a left-handed and right-handed configuration with an angle of about 50o between the metal axis and the helical electron cloud. In addition, it is observed that the electron cloud of some molecules reveal non-left and right hand but rather about 90o with the metal axis.

碩士
輔仁大學
化學系
107
In this report, we focus on the behaviors of target complexes [Ru(bpy)n(HDPA)3-n]2+ (n=1, 2) where bpy = 2,2’-bipyridine, HDPA = 2,2’-dipyridylamine. For the 298 K absorption spectra of all complexes, the low energy metal-to-ligand charge transfer (MLCT) transitions are located in the ranging of 400~500 nm. For 298 K and 87 K base titration absorption spectra [Ru(bpy)2(HDPA)]2+/[Ru(bpy)2(DPA-)]+ processes, we observed various MLCT band changing in range of 400~600 nm with isosbestic point at 452 nm and 473 nm, then the new absorption band formed in range of 500~600 nm for [Ru(bpy)2(DPA-)]+. The 77 K emission spectra and lifetime fitting of [Ru(bpy)2(HDPA)]2+ represents two-exponential decay phenomenon, and these attributed to dual triplet emitting states of 3MLCT (Ru-bpy) and 3ππ* (HDPA). The remarkably complicated excited state relaxation of [Ru(bpy)2(DPA-)]+, the 473 and 532 nm laser excitation due to the two-kind dual emission of [Ru(bpy)2(HDPA)]2+ (high energy region), and of [Ru(bpy)2(DPA-)]+ (low energy region) excited states relaxations. Furthermore, the lower energy 589 nm excitation can only observe a dual emission of [Ru(bpy)2(DPA-)]+. The DFT calculation for NTO (natural transition orbital) of both [Ru(bpy)2(HDPA)]2+ and [Ru(bpy)2(DPA-)]+ indicate the low energy triplet excited state (at T1 geometry) represent the 3MLCT (Ru-bpy, T1) for [Ru(bpy)2(HDPA)]2+ and 3MLCT (Ru-bpy)/3ππ* (DPA-) excited state mixing for [Ru(bpy)2(DPA-)]+ relaxation behavior. Furthermore the high energy triplet excited states, [Ru(bpy)2(HDPA)]2+ (T7) and [Ru(bpy)2(DPA-)]+ (T6) at T1 geometry imply the dual emission phenomena of both complexes relating to 3ππ* (HDPA/DPA-) excited state emission. These complicated emission relaxation for [Ru(bpy)2(DPA-)]+ are attributed to two-kind of dual emitting states at low energy, and we consider that they are attributed to [Ru(bpy)2(HDPA)]2+* and [Ru(bpy)2(DPA-)]+ * relaxation.

La administración tópica de medicamentos en terapias oftalmológicas consiste en colocar el fármaco (generalmente una solución o suspensión) directamente sobre el ojo mediante goteo. Luego de esta aplicación el tiempo de residencia del fármaco en la película lagrimal es generalmente corto, típicamente entre 2 y 5 minutos, y durante este tiempo solamente se absorbe en el tejido corneal entre 1 y 10% de la dosis aplicada. El resto del fármaco es drenado hacia la circulación sistémica junto con la lágrima. Usualmente estas limitaciones son compensadas con la aplicación de dos o más dosis seguidas, espaciadas cada 5 minutos, a fin de alcanzar la dosis terapéutica en el tejido. Según la gravedad de la patología, puede que este procedimiento deba realizarse varias veces al día. Todo este proceso conlleva a que se produzcan fluctuaciones muy marcadas en los niveles del fármaco en los tejidos, pudiendo alcanzarse valores superiores o inferiores a los niveles terapéuticos requeridos. Además, el uso de gotas oculares está asociado a una rápida variación en la velocidad de administración del fármaco a la córnea, lo cual a su vez limita la eficacia del sistema terapéutico. Si bien la administración tópica clásica mediante gotas (colirios) es de fácil aplicación y presenta menos complicaciones potenciales que otros sistemas de administración tópica (inyecciones, insertos, etc.), no es posible tener un control adecuado de la administración del fármaco ya que no permite controlar los niveles alcanzados con sucesivas aplicaciones durante todo el periodo de tratamiento. Por otra parte la absorción sistémica del fármaco a través del drenaje lagrimal genera una distribución del mismo en tejidos no específicos y evita el pasaje por el hígado, pudiendo causar efectos adversos sistémicos importantes, en especial cuando se administran de manera crónica. Con el objetivo de mejorar la absorción del fármaco en el sitio de acción o de absorción específico se han desarrollado estrategias alternativas que permiten aumentar su tiempo de permanencia en el ojo. Estos sistemas se denominan sistemas de transporte y liberación controlada de fármacos y se basan en la posibilidad de localizar el fármaco o la droga justamente en el sitio de acción y suministrar la cantidad necesaria durante el tiempo requerido, con el propósito de mejorar la biodisponibilidad y disminuir los efectos no deseados. Los sistemas de transporte y liberación de medicamentos son diseñados para regular la velocidad de liberación del fármaco, mantener una concentración terapéutica estable en el organismo, y evitar que se produzcan fluctuaciones importantes en sus niveles plasmáticos. En este caso la frecuencia de dosificación disminuye, se reduce el peligro de sobredosificación, se mejora la absorción, se alcanza un mayor tiempo de residencia y se producen menos efectos secundarios. La liberación de la droga a partir de estos sistemas puede ser constante durante un dado período o bien puede estar promovida por la acción de un determinado factor del entorno. Dentro de los sistemas alternativos para la administración de medicamentos oculares se encuentran las formulaciones semisólidas (geles), los ungüentos, los sistemas coloidales, los insertos y las lentes de contacto. Estos sistemas incrementan significativamente la eficiencia de las terapias oculares. Sin embargo presentan algunos inconvenientes como ser: visión borrosa en el caso de geles y ungúentos, problemas de colocación y expulsión, como sucede con los injertos. En el caso de las lentes de contacto, además de prolongar el tiempo de permanencia, también mejora la absorción, ya que su dimensión y ubicación (frente a la córnea) permite un contacto íntimo con la superficie corneal. Además presentan la ventaja de no interferir con la visión del paciente, no son expulsadas del ojo y en general presentan un alto confort. Las lentes de contacto adecuadas para estos fines son las denominadas “blandas” y son fabricadas empleando hidrogeles poliméricos ligeramente entrecruzados y se las conoce como lentes de contacto terapéuticas. Estas lentes de contacto terapéuticas, son preparadas fácilmente como sistemas de liberación mediante la inmersión de la lente en una solución de la droga o principio activo y actuando como reservorio. Las lentes de contacto de hidrogel han sido propuestas desde 1965 como posibles dispositivos para liberación o delivery de drogas. Sin embargo la mayoría de los estudios realizados desde esa fecha apuntan al estudio de la eficiencia que presentan las lentes de contacto blandas, diseñadas para otros fines (corrección óptica) como reservorio de medicamentos. Los inconvenientes que se presentan con las lentes de contacto blandas comerciales como sistemas de liberación controlada es su baja afinidad y capacidad de captar diferentes tipos de fármacos. Asimismo, en los casos donde la carga del fármaco en el hidrogel es adecuada, su mayor limitación radica en que la liberación para algunos fármacos ocurre demasiado rápido como para mantener niveles terapéuticos en las estructuras oculares durante períodos de tiempo suficientemente largos. En los últimos años se ha puesto mayor énfasis en la innovación tecnológica de lentes de contacto diseñados específicamente para sistemas de liberación de fármacos, debido en parte a los avances realizados en la comprensión de los mecanismos involucrados en los procesos de liberación, y al desarrollo y aplicación de nuevas estrategias orientadas a mejorar la capacidad de carga y el desempeño de estos sistemas. El comportamiento ideal de un sistema de liberación controlada o delivery de fármacos debería ser tal que pudiese regular la velocidad de liberación de forma tal de administrar la cantidad apropiada de fármaco, en el lugar adecuado y en el momento necesario. Una estrategia aplicada recientemente en el campo de la tecnología farmacéutica para el desarrollo de sistemas de transporte y liberación controlada de fármacos es el uso de hidrogeles responsivos, materiales con grupos funcionales capaces de modificar su estructura en respuesta a estímulos externos. En este marco, la aplicación de hidrogeles responsivos se basa en la posibilidad de que estos materiales modifiquen sus estructuras ante cambios del entorno, provocados por la presencia de un estado patológico, por requerimientos biológicos fluctuantes o por la aparición de ciertas biomoléculas, y liberen la cantidad apropiada del principio activo (fármaco) en función de la magnitud de ese cambio. La ventaja de emplear estos materiales radica en que se combinan las propiedades características de los hidrogeles con el potencial de regular la captación o liberación de sustancias en respuesta a cambios producidos en el entorno. El objetivo de este trabajo es sintetizar hidrogeles responsivos para su aplicación como sistemas de transporte y liberación de fármacos oculares de forma tal que permitan aumentar los tiempos de permanencia del fármaco en contacto con los tejidos oculares y lograr ejercer un control efectivo en la velocidad de liberación del mismo. Como se expuso previamente, esto permitirá: aumentar la absorción del fármaco, mejorar la biodisponibilidad, minimizar los efectos secundarios, disminuir la frecuencia de dosificación, evitar múltiples aplicaciones por dosis y mejorar el cumplimiento de la pauta terapéutica por parte de los pacientes. Particularmente, en este trabajo la elección del material se orientó hacia la posibilidad de modular la velocidad de liberación del fármaco en respuesta a pequeños cambios en el valor del pH lagrimal. A partir de copolimeros de dos monómeros acrílicos, 2-hidroxietil metacrilato (HEMA) y 2-(diisopropilamino)etil metacrilato (DPA), esperamos obtener un material, que presente por un lado propiedades compatibles para ser uso en la fabricación de lentes de contacto; y por otro lado que posea propiedades pH responsivas que permitan ser utilizados como sistemas para modular la liberación de fármacos y en particular en terapias oftalmológicas. El presente trabajo está organizado en capítulos. En el capítulo I se introduce el tema con una breve exposición de los conceptos generales sobre la administración de fármacos oculares y las vías de absorción. También se definen los sistemas de liberación controlada, sus características, y particularmente se describen las ventajas y desventajas del empleo de lentes de contacto terapéuticas y las posibilidades de emplear sistemas responsivos. En el capítulo II se describe de forma general la síntesis de los hidrogeles y los materiales y métodos empleados para la misma. En el capítulo III se estudian las propiedades fisicoquímicas de los hidrogeles sintetizados empleando diferentes técnicas de caracterización. Se estudian las características espectrales, las propiedades térmicas y las características superficiales. Como caracterización específica para su potencial aplicación se estudian las propiedades ópticas, la humectabilidad, el contenido acuoso y la densidad, a fin de determinar si los mismos son compatibles con su uso como lente de contacto terapéutica. En el capítulo IV se estudia el comportamiento de los copolímeros HEMA/DPA como sistemas de captación y liberación de principios activos, y su capacidad de controlar la velocidad de liberación a través de cambios en el pH del medio. En primer lugar se realiza un estudio sobre la capacidad de incorporar diferentes principios activos en diferentes condiciones de carga (pH y concentración de la solución de carga); en segundo lugar se analizan las interacciones entre algunos principios activos incorporados y la matriz de los polímeros; y en tercer lugar se estudia la capacidad de liberar los principios activos incorporados. A partir de éstos se determinan los tiempos y las cantidades de compuestos liberados en diferentes condiciones de pH y para las distintas composiciones y grados de entrecruzamiento de los hidrogeles. En el capítulo V se detallan las conclusiones generales de este trabajo y en el capítulo IX se plantean actividades y líneas de estudio que pueden ser motivo de trabajos futuros.

碩士
亞洲大學
生物資訊學系碩士在職專班
98
Diabetes affects the health conditions of at least 200 million people worldwide, and one person died from diabetes every 10 second around the world; IDF expects that by 2025, the death will increase to 3300 million.In Taiwan, the cause of death statistics announced by the Department of Health, Taiwan in year 98, showed that the diabetic has become the fifth leading cause of death, and accounted for 5.8% of overall mortality (Taiwan Department of Health, 2009); diabetes have become one of chronic diseases so that the bad control of diabetes would cause many complications. The latest two oral hypoglycemic medicines (Dipeptidyl Peptidase-IV Inhibitor) introduced into Taiwan, the pyrrolidine derivatives, can inhibit the activity of DPP IV, avoid endogenous GLP-1 (glucagon-likepeptide-1), and the breakdown of GIP (glucose-dependent insulinotropic polypeptide) to reduce high blood sugar, not to affect body weight, and easily to lead to low blood sugar level.

Tese de mestrado, Epidemiologia, Universidade de Lisboa, Faculdade de Medicina, 2015
Regarding this work an actualization has been made to the thesis delivered in January of 2015. As this is a field of rapid evolution a new systematic review has been made in May 2015 with the retrieval of new studies published in the years of 2014 and 2015. This new review did not change the methods and conclusions from the former one. The objectives are to conduct a systematic review of cost-effectiveness, cost-utility and cost-benefit studies of DPP-4 inhibitors for diabetes treatment versus other antidiabetics. Regarding the methods three investigators searched the CRD York, Tufts CEA Registry, MEDLINE databases through May 2015. We revised all potentially relevant titles and abstracts, and subsequently screened full-text articles, according to inclusion criteria. The studies should be available as a full-text publication and published in English, French, Spanish, or Portuguese. A critical appraisal of the methodology and reporting was performed using the 35 item version of the BMJ checklist. Regarding the results a total of 295 studies were identified, of which 20 after the 2nd screening. Compared to sulphonylureas, the ICER varied between €924-13,931/QALY for saxagliptin, €5,949-20,350/QALY for sitagliptin and €9,072/QALY for vildagliptin, all as add-on to metformin. Compared to insulin, saxagliptin presented an ICER of €6,100/QALY (with sulphonylurea) and €6,790/QALY (with metformin). Compared to sitagliptin, liraglutide had an ICER that varied between €10,436-32,869/QALY as second line therapy. Finally, a study on GLP-1 agonists established an ICER of €37,463/QALY versus DPP-4 inhibitors. The majority of the studies were based on clinical trials of high quality; differences in ratios were essentially due to differences in the costs of resources across countries. Finally the conclusions are that according to commonly accepted thresholds, DDP-4 inhibitors are cost-effective versus sulphonylureas, and liraglutide versus sitagliptin for diabetes type 2. Recent evidence demonstrates that GLP-1 agonists are cost-effective versus DPP-4 inhibitors, possibly questioning the national current therapeutic guidelines.
Em 2013 estima-se que 382 milhões de pessoas tinham diabetes a nível global. (1). De acordo com a Federação Internacional da Diabetes, 5.1 milhões de pessoas morreram de diabetes em 2013. Os países onde a prevalência é maior entre os 20-79 anos de idade são os de médios e altos recursos. Os inibidores das DPP-4 são medicamentos relativamente novos. A Sitagliptina, saxagliptina, linagliptina, vildagliptina e alogliptina estão aprovadas pela FDA e pela EMA, enquanto outros aguardam aprovação de AIM ou estão em desenvolvimento. A guideline do NICE para a diabetes tipo 2 sugere adicionar um inibidor das DPP-4 em vez de uma sulfonilureia como tratamento de segunda linha, com metformina em primeira linha, se existe um risco considerável de hipoglicemia ou se a sulfonilureia está contra-indicada ou não é tolerada. Esta recomendação é baseada numa revisão sistemática da Cochrane, com um pequeno número de ensaios, todos publicados antes de 2009, e apenas relacionados com sitagliptina e vildagliptina. Além disso, esta guideline não incorpora considerações de custo-efectividade relativas aos novos inibidores das DPP4, que são no entanto essenciais como um instrumento para ajudar a decisão de alocação de recursos. A importância é enfatizada em contextos correntes de recessão económica e de pressão nos budgets públicos já de si apertados, e considerando os altos burdens epidemiológico e económico da doença em questão. O objectivo deste estudo foi conduzir uma revisão sistemática de estudos custoefectividade, custo-utilidade e custo-beneficio de inibidores das DPP4 versus outros antidiabéticos como tratamento da diabetes tipo 2, e perceber as suas implicações para guidelines, politicas e futura pesquisa.

碩士
國立臺灣大學
材料科學與工程學研究所
94
We prepared poly[2-(2-ethylhexyloxy)-5-methoxy-1,4-phenylene vinylene ]-block-poly(2,3-diphenyl-5-octyl-p-phenylene vinylene(MEH-PPV-block- DPO-PPV) with MEH-PPV and DPO-PPV chain segments by Wittig-Horner reaction in this research . When this two polymer chian segments reach the saturation of conjugation length, it make diblock copolymer have better luminescence efficiency than pure MEH-PPV and DPO-PPV.Besides, we also prepared pure MEH-PPV and DPO-PPV for comparison . We used NMR to characterize these three polymer structures and DSC 、TGA to investigate their thermal properties. We synthesized successfully MEH-PPV 、DPO-PPV and their diblock copolymer by controlling the reaction temperature and time.In THF solution, DPO-PPV appeared blue-green,MEH-PPV orange-red and MEH-PPV-block- DPO-PPV yellow.The three polymers all exhibited bright photoluminescence.Wittig-Horner reaction is the condensation reaction of aldehyde and phosphonate ,but can’t synthesize higher molecular weight.Polymer with small molecular weight can’t form smooth film after spin coating instead the film had molecular defects that would affect luminous properties. As we fabricated polymer light emitting diodes(PLED),MEH-PPV has turn-on voltage at 3.9V and the largest luminance of 102 cd/m2 at 12.2V.MEH-PPV-block-DPO-PPV has the best efficiency among three polymers with the turn-on voltage at 3.1V,and has the bright luminance of 525cd/m2 at 9V.

博士
國立交通大學
材料科學與工程學系所
102
I Abstract Synthesis of Naphthalimide Derivative and Diketopyrrolopyrrole (DPP)-Based [2]Rotaxane/Polyrotaxane as Novel Chemosensor Materials and a Controllable Hierarchical Nano Self-Assembled Structure from Polyrotaxane Student: M. V. P. S. K. R. Raju Advisor: Hong-Cheu, Lin The pivotal objective of this dissertation is to construct novel orthogonally H-bonded mechanically interlocked molecular/polyrotaxane architectures with an asymmetric (Diketopyrrolopyrrole) stopper and to study their molecular shuttling process under solvent, anion, and acid-base stimuli control along with their controllable hierarchical nanostructure formations plugged with positive cooperativity non-covalent interactions. In the introduction of this doctoral thesis we have introduced brief early synthetic attempts to create mechanically interlocked molecules (MIMs) such as rotaxanes and catenanes as well as their polymeric counterparts. Moreover novel templating methodologies to build MIMs and some latest examples of MIMs based molecular shuttles under various stimuli control were also introduced. Fundamentally, underplayed chemo sensing mechanisms in these systems were presented. Meanwhile, we have developed a novel and facile fluorescent ratiometric chemodosimeter for grisly toxic hydrazine via mild Ing-Manske phthalimide deprotection method in this doctoral thesis as well. In chapter two, a novel [2]rotaxane based on an orthogonal H-bonded motif and 3,6-di(thiophenyl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione (DPP) with controlled topicity was successfully constructed, displaying excellent stimulated responses toward anion and solvent polarity. The extensive 1H &; 19F NMR titrations were lucidly revealed the binding site and the mode binding interaction as well. The preorganized host selectively recognized F- with high optical sensitivity and reversibility via enhanced positive cooperativity and noncovalent interaction by evidence of a shorter fluorescence lifetime. Therefore we developed a first prototype [2]rotaxane molecular shuttle for selective recognition of F- with high optical outputs. II In chapter three, four analogous polymers were systematically synthesized by copolymerization of a 9-alkylidene-9H-fluorene monomer with various monomers, which contained a diketopyrrolopyrrole unit tethered with a dumbbell unit, a metalated [2]rotaxane, a demetalated orthogonal H-bonded [2]rotaxane, and a simple alkyl chain, to furnish P1, P2, P3, and P4, respectively, to investigate the supramolecular interactions of the mechanically interlocked rotaxane pendants and conjugated polymer backbones. Prevailing 1H NMR and UV-vis to NIR titration profiles indicated that the novel polyrotaxane P3 showed a sensitive and reversible acid-base molecular switch capability via supramolecular interactions in contrast to the other polymers (P1, P2, and P3). Compared with the other polymers, P3 possessed a narrower bandgap, which was also confirmed by the computational study. Prominently, the monitoring of a controllable nano-self-assembly process of P3 was obtained by reversible acid-base molecular switch approaches. The orthogonal H-bonded pendant [2]rotaxane unit and the steric demand of P3 judiciously allowed to morph into a hierarchical nanostructure via interconvertible H-bonds, anion-π and π-π stackings, as well as hydrophobic interactions. In chapter four, A facile and sensitive fluorescent probe for hydrazine based on phthalimide appended hydrophilic naphthalimide was successfully constructed, displaying excellent colorimetric and ratiometric responses towards hydrazine via Ing-Manske phthalimide deprotection conditions in semi-aqueous buffer solution. The estimated detection limit was as low as 4.2 nM (hydrazine content = 1 ppb) far below than the threshhold limit value (TLV) of 10 ppb according to the U. S. Environmental Protection Agency (EPA). Prevailing detection of hydrazine in living cells of the current probe is demonstrated. Thus in conclusion, a novel archetype DPP based highly fluorescent [2]rotaxane was developed. The remarkable stimulated responses towards solvent polarity and fluoride ion were discussed. Moreover, the extended efforts of this current design into polyrotaxane architectures along with their acid-base controllable hierarchical nanostructure formations via reversible optical molecular switch approaches coupled with various non-covalent interactions were discussed. Furthermore a novel fluorescent ratiometric chemodosimeter for hydrazine based on Ing-Manske phthalimide deprotection was presented in detail.

博士
亞洲大學
生物資訊與醫學工程學系
104
Dipeptidyl peptidase-4 (DPP-4) is the vital enzyme responsible for inactivating intestinal peptides Glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP), which stimulates a decrease in blood glucose levels. The aim of this study was to explore the inhibition activity of small-molecule inhibitors to DPP-4. AutoDock, CDOCKER and Standard dynamics cascade were used for molecular docking and molecular dynamics studies. Molecular docking was performed for structurally diverse compounds (Aminopiperdine-fused imidazoles, Thiazolopyrimidine derivatives, and quinolin-fused imidazoles) and the differences in their binding modes were investigated. Furthermore, good correlation (R2=0.72) was acquired for the DPP-4 inhibitors based on the predicted binding affinities (pKi) determined by using AutoDock, CDOCKER and experimental activity values (pIC50). Based on molecular docking receptor-ligand interactions, pharmacophore generation was carried out to determine the binding modes of structurally diverse compounds in the receptor active site. Study of the stability and flexibility of the DPP-4 inhibitor complexes by means of MD simulation specified that the inhibitors retained the binding mode observed in the docking study. The present studies provides some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors discoveries in treatment of type-2 diabetes.

Trabalho de revisão do 6º ano médico com vista á atribuição do grau de mestre (área científica de farmacologia) no âmbito do ciclo de estudos de Mestrado Integrado em Medicina.
Abstract Incretins are gastrointestinal-derived hormones released in response to a meal that play a key role in the regulation of postprandial secretion of insulin (incretin effect) and glucagon by the pancreas. Both incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have several other actions. GLP-1 regulates body weight by inhibiting appetite and delaying gastric emptying, actions that are dependent on central nervous system GLP-1 receptor activation. Several other hormones and gut peptides, including leptin and ghrelin, interact with GLP-1 to modulate appetite. GLP-1 is labile, being rapidly degraded by dipeptidyl peptidase-4 (DPP-4), a multifunction molecule whose role in obesity dynamics extends beyond incretin metabolism. DPP-4 is involved in adipose tissue inflammation, which is a pivotal event in insulin resistance and a key pathophysiological mechanism in the genesis of obesity-related complications. Furthermore, the incretin system appears to provide the basis for understanding the high weight loss efficacy of bariatric surgery, a current employed obesity treatment that also benefits diabetes. The present review brings together new insights into obesity pathogenesis, integrating GLP-1 and DPP-4 in the complex interplay between obesity epidemics and inflammation, namely in diabetic patients. This will in turn provide the basis for new perspectives regarding GLP-1 receptor agonists and DPP-4 inhibitors therapeutic potential.